Methods for the treatment of emesis



Unitcd States Patent 3,415,934 METHODS FOR THE TREATMENT OF EMESISMichel Leon Thominet, Paris, France, assignor to Societe dEtudesScientifiques et Industrielles de lIle-de-France, Paris, France N0Drawing. Continuation-impart of application Ser. No. 210,555, July 17,1962. This application Sept. 20, 1967, Ser. No. 669,297

Claims priority, application France, July 25, 1961, 869,013, 869,014 6Claims. (Cl. 424--274) ABSTRACT OF THE DISCLOSURE Emesis in mammals issignificantly decreased or substantially removed by the administrationof certain substituted indoles and indolines. Treatment may be givenorally or parenterally.

CONIIWN in which R, and R are lower alkyl groups, such as the methyl,ethyl, propyl or isopropyl group; W is an alkylene group of- 2-4 carbonatoms, such as the ethylene, propylene, methyl ethylene or 2*methylpropylene group; and A is a lower alkoxy group, such as methoxy, ethoxy,isopropoxy or butoxy.

The substituted carboxamide indoles are produced by reacting a loweralkyl ester of 3-hydroxy-2-indolyl formic acid with a lower alkylatingagent in acetone in the presence of potassium carbonate, treating theresulting reaction product with the reqiured disubstituted diamine inboiling toluene, recovering the alcohol formed in the course of thereaction, expelling the solvent, acidifying, reprecipitating the base byadding an alkali to the acid solution and forming a salt of thecarboxamide by reacting in an inert solvent an acid with the dissolvedbase. For the hydrochloride, for instance, a stream of gaseous dryhydrogen chloride is caused to pass into an isopropyl alcohol solutionof the base.

For example, the reacting of the preparation of the 3-methoxyindole-Z-N-(diethyla minoethyl) carboxamide is indicated asfollows:

OH dimethyl sulfate acetone potassium -oooorn carbonate) \N [00001133,415,934 Patented Dec. 10, 1968 To obtain the corresponding indolinesfrom the substituted carboxamide indoles, hydrogenation is etfectuatedin an autoclave under pressure and heat in the presence of a knowncatalyst such as platinum or palladium carbon in an inert solvent likealcohol. The solvent is expelled after hydrogenation and the residue isrecrystallized. Salts of the substituted indoline base may be obtainedby treating the base in solution in an inert solvent with the requiredacid. To chain the hydrochloride, for example, the base is dissolved inisopropyl alcohol and a current of gaseous dry hydrogen chloride ispassed into the alcoholic solution.

The substituted carboxamide indoles, the corresponding indolines andtheir salts of this invention possess significant pharmacologicalproperties and may be used for the treatment of emesis associated withmany conditions, such as pregnancy and seasickness, and behaviordisturbances. For this purpose, the substituted indoles, substitutedindolines or their salts may be incorporated in or combined withpharmaceutically acceptable carriers.

Examples of the preparation of specific substituted indoles and acorresponding substituted indoline are as follows:

Preparation I.-3-methoxyindole-2-N-(diethylaminoethyl) -carboxamidehydrochloride 91 grams of methyl-3-methoxyindole-2-carboxylate and 103grams of diethylaminoethylamine are dissolved in cc. of toluene. Thesolution is heated to boiling, and the methanol formed in the course ofthe reaction, which requires 22 hours, is removed.

The resulting 3-methoxyindole-2-N-(diethylaminoethyl) carboxamide isdissolved in about 5 00 cc. of water, is acidified and the aqueous acidsolution extracted with ether. The base is precipitated by the additionof ammonia to the acid solution, 1s filtered and recrystallized in 95%ethanol. There are obtained 102 g. of a bright yellow product having amelting point of 117-118" C. The hydrochloride of that base is preparedby dissolving the base in isopropyl alcohol and passing into that solution 13 g. of gaseous dry hydrogen chloride. There are obtained 111grams of 3-methoxyindole-2-N-(diethylaminoethyl) carboxamidehydrochloride having a melting point of 173-174 C.

Preparation II.-3-ethoxyindole-2-N- (diethylaminoethyl carboxamidehydrochloride 124 grams of ethyl-3-ethoxyindole-Z-carboxylate and 126grams of diethylaminoethylamine are boiled with cc. of xylene for 22hours. The alcohol formed in the course of the reaction is removed. Thereaction product is dissolved in about 500 cc. of water, acidified, andthe aqueous acid solution is extracted with ether. The base isprecipitated by the addition of ammonia. By recrystallization in 95%ethanol, 125 grams of a white product is obtained, having a meltingpoint of 141142 C.

The hydrochloride of the base is prepared by dissolving this base inisopropyl alcohol and passing through it 15 grams of gaseous dryhydrogen chloride. There are obtained 132 grams of3-ethoxyindole-2-N-(diethylaminoethyl) carboxamide hydrochloride havinga melting point of 160-161 C.

Preparation III.-3-ethoxyindoline-2-N-(diethylaminoethyl) carboxamidehydrochloride 50 grams of 3-ethoxyindole 2 N-(diethylaminoethyl)carboxamide are dissolved in 200 cc. of 95 ethanol and hydrogenated inan autoclave under heat and pressure with 10 grams of palladium carbonas a catalyst. After hydrogenation is terminated, the catalyst isfiltered, the alcohol evaporated and the residue recrystallized inisopropyl alcohol. There are obtained 40 grams of product, having amelting point of 909l C. The hydrochloride of that base is prepared bydissolving the base in isopropyl alcohol and passing through a currentof gaseous hydrogen chloride. There are obtained 34 grams of3-ethoxyindoline-Z-N-(diethylaminoethyl) carboxamide hydrochloridehaving a melting point of 151-152 C.

If a pharmaceutically acceptable salt other than the hydrochloride isdesired, the substituted indole carboxamide or substituted indolinecarboxamide base is reacted preferably under anhydrous conditions withthe required acid. For example, such base may be reacted with sulfuricacid, tartaric acid or phosphoric acid.

The toxicities studied in mice establish that the compositions of thepreparation each have a toxicity suitable for therapeutic use. Thetoxicities of the three compositions are given in the following table:

DL in mg. per kg. Composition: of body weight Composition #1,3amethoxyindole 2 N-(diethylam'inoethyl) carboxamide 40 Composition #2,3-ethoxyindole-2-N-(diethylaminoethyl) carboxamide 37.5 Composition #3,3-ethoxyindoline 2 N-(diethylaminoethyl) carboxamide 34 The followingtable shows the intraperitoneal and subcutaneous toxicities of suchcompositions.

DLto (mouse) in mg. per

The antiemetic action of these compositions on the centers of vomitinghas been studied in dogs in conjunction with apomorphine in accordancewith the technique of Chen and Ensor, Journal of Pharmacology andExperimental Therapeutics, vol. 98, pp. 245-50, 1950, as modified byDucrot and P. Decourt, Compt. Rendu. Soc. Biol., vol. 145, pp. 356-8,1951. Four dogs were used in the test.

In this testing, two dogs were used as controls, i.e., two dogs in whichapomorphine were injected but which were not treated by the preparationbeing studied. The preparation being tested was administeredsubcutaneously to the treated dogs 30 minutes before administration ofthe 0.10 milligram of apomorphine per kilogram of body weight of thedog. Thirty minutes thereafter, all of the dogs, treated and untreated,were administered 0.10 milligram of apomorphine per kilogram of bodyweight. The vomitings 'were counted for a 30 minute period following theinjection of the apomorphine. The results of the testing with the dogsusing the controls as the benchmark for the determination of theprotection afforded by the three preparations is given in the followingtable:

Dosage of composition used Composition Greater than 2.5 mg. 2.5 mg. perkg. of

per kg. of body weight bony weight (percent- (percentage of ego ofprotection) protection) (a) Sugar coated 25 mg. tablets at the rate of 6to 8 daily;

(b) Injectable ampoules or aqueous solutions for use in aerosol or othersprays in dosages of mg. per 2 cc. of solution at the rate of 2 to 4doses daily;

(c) Suppositories of 100 mg. at the rate of 2 to 4 daily;

((1) Granulated sucrose for babies at 10 mg. per dose,

equivalent to one full level teaspoon (about 4 g);

(e) Sugar syrup for babies at a dosage of 10 mg. per teaspoon of 5 cc.

The duration of the treatment and the dosages utilized vary with theillness treated. With mammals having the Weight span of man, thedesirable daily dosage is in the range of 10 to 800 mg. Such treatmentand dosage in a particular situation would be determined by aprofessional skilled in the art of the prevention cure, and alleviationof disease, illness and injury of mammals.

What is claimed is:

1. The method of treating emesis in mammals, said method comprisingadministering to a mammal 1 to 5 mg. per kg. of body weight of saidmammal of a compound selected from the class consisting of substitutedindole carboxamides, non-toxic acid addition salts of said indolecarboxamides, corresponding indoline carboxamides and non-toxic acidaddition salts of said corresponding indoline carboxamides, saidsubstituted indoles being of the formula:

-CONHWN i R H in which A is lower alkoxy; W is alkylene of 2-4 carbonatoms; and R and R are lower alkyl.

2. The method in accordance with claim 1, in which the daily dosage is10 mg. of 800 mg. of the compound.

3. The method in accordance with claim 1, in which a single dosage is 1mg. to mg. of the compound.

4. The method in accordance with claim 1, in which the compoundadministered is a non-toxic acid addition salt of3-methoxyindole-2-N-(diethylaminoethyl)carboxamide.

5. The method in accordance with claim 1, in which the compoundadministered is a non-toxic acid addition salt of 3-ethoxyindole-2-N-diethylaminoethyl carboxamide.

6. The method in accordance with claim 1, in which the compoundadministered is a non-toxic acid addition salt of3-ethoxyindoline-2-N-(diethylaminoethyl)carboxamide.

(References on following page) References Cited UNITED STATES PATENTSClinton et a1. 260-559 Coenen et a1. 260-319 Albertson 260-319 Toplisset a1. 167-65 Kuna et a1. 167-65 6 OTHER REFERENCES Elderfield:Heterocyclic Compounds, vol. 3, pp. 115- 116 (1952).

Wormser et al.: J. Pharm. Sci., 5 (1961).

vol. 50, pp. 976-977 ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,415,934 December 10 1968 Michel Leon Thominet It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 3, in the table, first column, line 1 thereof, "Cokposition"should read Composition Column 4, line 40, "prevention cure should readprevention, cure H lines 51 to- 56 the right-hand portion of the formulareading:

R R l l N should read N same column 4 line 60 "of", first occurrenceshould read to line 62 "1" should read l0 Signed and sealed this 24thday of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E SCHUYLER, JR.

Attesting Officer Commissioner of Patents

